The long term objective of this study is to identify novel molecules as potential clinical candidates for the inhibition of HIV-1 integrase (IN) and the prevention of HIV-1 replication. Cellular chromatin-tethering LEDGF fusion protein was reported to be essential in HIV replication through an association with IN, making it an ideal target for antiviral therapy. The proposed studies aim to design pharmacophore-based models to mine molecular databases for novel compounds that will disrupt IN-LEDGF complex formation. Specific aim I is directed at using crystallography data as a platform to design site-specific IN inhibitors with a novel mechanism independent of catalytic site. Initial sets of compounds identified from IN-LEDGF complex models will provide future activity-based models to enhance discovery for additional lead molecules. Specific aim II is designed to filter subpopulations of IN and LEDGF antagonists with favorable physiochemical properties predicted in ADMET simulations to generate new Q-SAR models that will aim to identify new inhibitors showing activity in vivo. Specific aim III is designed to determine the synergistic effects of identified IN inhibitors in combination with known anti-HIV compounds in vitro and in cell-based assays. AIDS is one of the world's most serious health problems. In 2005, the world health organization and the U.S. government created a joint effort to increase the availability of antiretroviral drugs to developing countries as the CDC announced HIV had reached one million infections in the U.S. Between 2004 and 2006, there was a 16.7 % increase in the number of AIDS patients in North America, compared with a 4.7 % increase in Sub-Saharan Africa, a 5.6 % in South East Asia, and 21 % increase in East Asia as reported by a joint United Nations Program on HIV/AIDS (UNAIDS). Without an effective antiviral regimen HIV subjects will eventually succumb to HIV-1 immunodeficiency. PUBLIC HEALTH RELEVANCE: The emergence of drug resistant viral strains and the exponential increase in HIV-1 infections worldwide echoes an urgency to develop new HIV-1 therapeutics with novel mechanisms of action to incorporate into HAART drug regimes.